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Our regular review of pharmacotherapy

Various

British Journal of Family Medicine, 1 (2), September, 2013

Emergent therapies

Apixaban shows promise for VTE treatment

Results from Phase 3 AMPLIFY trial of over 5,000 patients with acute venous thromboembolism (VTE) have shown that single agent treatment with the oral anticoagulant apixaban (Eliquis) achieved equivalent efficacy and significantly lower rates of major bleeding, compared with conventional therapy. Apixaban is currently available in the UK for the prevention of stroke in patients with atrial fibrillation (AF)and in adult patients who have undergone elective hip or knee replacement surgery. These latest data, along with results from AMPLIFY-EXT, published earlier this year, have prompted the co- developers Bristol-Myers Squibb and Pfizer to file for an extended licence for the treatment of VTE.

SMC recommends abatacept for RA

The Scottish Medicines Consortium (SMC) has announced that abatacept solution for subcutaneous injection (Orencia SC) has been accepted for use within NHS Scotland, in combination with methotrexate (MTX), as a first-line biologic agent for adults with severe rheumatoid arthritis (RA) after failure with conventional disease modifying anti- rheumatic drugs (DMARDs). Around 400,000 people currently have rheumatoid arthritis in the UK, forcing approximately a third of people with the condition to stop work within two years of its onset.

The SMC recommendation means that abatacept is now the only biologic available in NHS Scotland in both self-injectable subcutaneous (SC) and intravenous (IV) formulations, offering a rational alternative to anti-TNFs. It also enables the use of abatacept earlier in the treatment pathway, providing clinicians with greater treatment options. Abatacept, in combination with MTX, is licensed for the treatment of moderate to severe active RA in adult patients who have responded inadequately to previous DMARD therapy.

In April this year, NICE finally approved the use of abatacept with methotrexate in England as an option for RA in cases where the disease has responded inadequately to two conventional non-biological DMARDs including methotrexate.

Regulatory news

Expert bodies support continued use of GLP-1 therapies

The recent joint investigation by the BMJ and Channel 4’s Dispatches current affairs programme, which pointed to the possibility that GLP-1-based therapies may cause pancreatic damage, has prompted the Association of British Clinical Diabetologists (ABCD) to issue a position statement on GLP-1-based therapies. While a plausible mechanism was proposed by which GLP-1-based therapies might lead to pancreatitis and even pancreatic cancer, the ABCD has questioned the design of the study and the validity of the data supporting the proposal. “The single observational study in support of the hypothesis that GLP-1- based therapies cause pancreatitis is open to criticism and is not supported by other such observational studies. The animal data… is inconsistent and the human histological data is preliminary and open to alternative explanations,” says the ABCD statement. “Results from studies involving adverse events reporting systems cannot be relied upon because of ‘notoriety bias’.”

Acknowledging that a cautious approach would “seem reasonable”, the statement points out that in nationwide audits, real-world use of GLP-1 receptor agonists (GLP-1RAs) was associated with improvements in glycaemic control and weight, with reduction in other diabetes therapies, in particular insulin. There were very few reports of pancreatitis, and 75% of these had an alternative explanation. The statement concludes: “The strength of the data in support of GLP-1-based therapies causing pancreatic damage does not justify the alarm that has been caused to patients taking these therapies.

By stopping these agents in response to the scare that has been created, harm to patients may occur because of the discontinuation of the agents in whom they were working well. “Pharmaceutical companies should make all relevant data available for inspection by independent experts.” The ABCD stance is supported by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), which has recently finalised a review of GLP-1-based diabetes therapies. The Committee concluded that presently available data do not confirm recent concerns over an increased risk of pancreatic adverse events with these medicines. Following a review of the publication and consultation of a panel of experts, the CHMP echoed the ABCD view that the supporting study had a number of “methodological limitations and potential sources of bias… which preclude a meaningful interpretation of the results”.

EMA warns against use of oral ketoconazole

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency’s (EMA) has stated that oral medicines containing ketoconazole (Nizoral) should no longer be used for the treatment of fungal infections.

The decision follows reports that some patients taking these medicines may be at an increased risk of liver damage, and the CHMP believes the risk outweighs the benefits. Alternative anti-fungal treatments are available.

The recommendation applies only to oral products; shampoos and creams containing ketoconazole are not affected by the decision.

Agents containing oral ketoconazole are not widely used in the UK, and these products already contain warnings about the risk of liver damage. CHMP advises that patients on these medicines should make a non-urgent appointment with their doctor to discuss alternative treatment.

Insomnia affects 'morning after' shopping

If fellow shoppers at the local supermarket appear somewhat torpid, look no further than the journal Obesity for an explanation. A research team from Uppsala University, Sweden report that a study group of men, when deprived of one night’s sleep, purchased more food on the following day – in terms of both calories and weight – than they did after a good night’s sleep.

Given the known tendency of insomnia to impair higher-level thinking and to increase hunger, the Uppsala researchers set out to test whether sleep deprivation had any bearing on an individual’s food purchasing choices.

In a bizarre variation of Supermarket Sweep, 14 study subjects were given a fixed budget of around £40 and instructed to purchase as much as they could out of a possible 40 items that included 20 high-caloric foods and 20 low-calorie foods. They went through this routine after a night of sleep deprivation and again after a normal night of sleep. When sleep-deprived, the men purchased significantly more calories (+9%) and grams (+18%) of food than they did after a night of sleep.

“Our finding provides a strong rationale for suggesting that patients with concerns regarding caloric intake and weight gain maintain a healthy, normal sleep schedule,” said research lead Dr Colin Chapman. Perhaps advisedly, he added that follow-up studies may be needed.

Smoking and asthma: a dangerous synergy

Certain assumptions about risks in pregnancy may seem so intuitive as to be hardly worth testing. But recent closer investigation has in fact thrown up surprising and useful data.

New research from the University of Adelaide has shown that pregnant women who have asthma and also smoke are at disproportionately greater risk of complications for themselves and their unborn children.

The study, claimed to be the first of its kind, compared data from more than 170,000 Australian women over 10 years. Analysis showed that 5.8% of pregnant women who were not asthmatic and non-smokers experienced a preterm birth. This rate rose to 6.5% in asthmatic non-smokers and 9.4% in non-asthmatic smokers. But in asthmatic women who also smoked, the rate of preterm birth soared to 12.7% – more than double the normal rate.

The findings, published online ahead of print in the European Respiratory Journal , provide “an alarming statistic”, according to lead author Dr Nicolette Hodyl. “We hope that pregnant women [with asthma] begin to understand the seriousness of this situation to their health and the health of their child,” she says.

Frentic mice hint at behavioural link to ear disorders

Parents and healthcare professionals will attest to the fact that children with inner ear disorders often display behavioural problems, but this is usually dismissed as an unsurprising result of discomfort and disorientation.

But now researchers in New York appear to have found a causal link between inner ear dysfunction and neurological changes that increase hyperactivity. Prompted by observations of overactivity in mice with severe cochlear and vestibular defects, researchers at the Albert Einstein College of Medicine hypothesised that inner-ear defects cause abnormal functioning of the striatum, the central brain area that controls movement. Tests in the affected animals revealed increased levels of two neurotransmitters involved in a signalling pathway within the striatum.

Administering a known inhibitor to one of these proteins restored locomotor activity to normal, but only in the overactive mice. According to the researchers, the findings suggest that hyperactivity in children with inner-ear disorders might be therefore controllable with medications that inhibit the signalling pathway in the striatum. “Our study also raises the intriguing possibility that other sensory impairments not associated with inner-ear defects could cause or contribute to psychiatric or motor disorders,” say the authors.

Obesity gene tests 'won't encourage fatalism'

The impending advent of gene testing to assess the risk of obesity is seen by some clinicians and dieticians as a mixed blessing, as it may prompt those with positive results to become fatalistic and reduce motivation to keep their weight down. But new data from University College London (UCL) may serve to quell their concerns.

Of the possible candidates studied, the gene known as FTO has been found to have the biggest influence so far. Those who inherit the A variant of the gene from both parents are 70% more likely to become obese than those with no A variant genes.

The UCL team used the gene test (which is not yet commercially available) to determine the FTO status of a small number of volunteers, who were then interviewed about their experience. The sample included men and women, who spanned the weight range from underweight to obese. Those who struggled with their weight said that the genetic test result was helpful because it removed some of the emotional stress attached to weight control and relieved some of the stigma and self-blame. But no one reported a negative reaction to the genetic test result, or said it made them feel there was nothing they could do to about their weight.

Susanne Meisel, who led the study said: “These results are encouraging, as they indicate that people are unlikely to believe that genes are destiny and stop engaging with weight control once they know their FTO status.”

The UCL team are now planning a larger study to confirm their findings.